PROJECT SUMMARY This is a request to the NIH/NIDCD for a Multi-Investigator-Initiated Research Project Grant (R01) Award for Thomas C. Bozza, PhD, Associate Professor of Neurobiology, and Jay A. Gottfried, MD, PhD, Associate Professor of Neurology, at Northwestern University. The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Disorders in the sense of smell are commonly observed in Alzheimer?s disease and Parkinson?s disease, with early accumulation of neuropathological lesions in the peripheral olfactory system including sensory neurons of the nasal mucosa and their projections to the olfactory bulb. Despite the critical contributions of these structures to olfactory perceptual processing, and their widespread involvement in neurodegenerative disorders, we have only a rudimentary understanding of the molecular and cellular components of the human peripheral olfactory system. Moreover, it remains unclear whether the wealth of information available about olfaction in model organisms applies to the anatomical, physiological, and functional properties of the human olfactory system. In research proposed here, we will leverage our complementary strengths in mouse olfactory genetics (Dr. Bozza) and human olfactory neurobiology (Dr. Gottfried) to comprehensively characterize the human peripheral olfactory system with a research breadth and specificity not previously attempted. This work will exploit advanced next-generation sequencing, novel ?trans vivo? gene targeting, immunohistochemistry, electrophysiology, in vivo calcium imaging, and access to human biopsy and post-mortem tissue samples, to study the expression, function, and topographical mapping of human odorant receptor genes. Specific experiments will (1) measure the expression and determine the structure of chemosensory genes including olfactory receptors (ORs) and trace amine- associated receptors (TAARs) in the human olfactory epithelium, (2) characterize the odor response profiles of human odorant receptors when expressed in mouse olfactory sensory neurons, and (3) define the spatial distribution of receptor-specific projections of human olfactory sensory neurons from the epithelium to the olfactory bulb. Together these studies will advance our understanding of the functional organization of the human olfactory system, and will set the stage for clarifying how individual chemoreceptor genes influence odor perception. Finally, by defining the functional organization of olfactory pathways in neurologically intact individuals, this work will serve as a valuable starting point for investigating the impact of neurodegenerative disease on olfactory gene expression, circuit anatomy and sensory function.